Memorial Sloan Kettering Cancer Center (MSKCC) is an NCl-designated Comprehensive Cancer Center with one of the largest hematopoietic stem cell transplant ( HSCT) programs in the country. The SCT program at MSKCC is a FACT-accredited program and is divided into pediatric and adult services. MSKCC has been a Core Member of the BMT-CTN since it's inception and Dr. Giralt as the new Chief of the Adult BMT Service as well as all members of the Adult BMT Service consider participation in the BMT-CTN an integral part of their mission. GVHD, both acute and chronic remains one ofthe most significant barriers to successful HSCT. Even when effectively treated the sequelae of GVHD or the side effects of chronic immune-suppressive therapy have significant negative impact on the quantity and quality of life of transplant survivors. Thus prevention of both acute and chronic GVHD should remain a major element in the BMT-CTN research portfolio. Only two acute GVHD prevention strategies have been shown to reduce the risk of chronic GVHD, T cell depletion (TCD) and post transplant cyclophosphamide (post transplant CY). For this BMT-CTN renewal application we hypothesize that TCD will be more effective than post transplant CY in preventing aGVHD and cGVHD after HLA matched HSCT in patients with AML or MDS and that these strategies differ in regards to immune-reconstitution and quality of life. We propose to demonstrate this through the conduction of a randomized phase II trial whose specific aims are: 1. Demonstrate that 6 month event free survival (6mEFS) (events being defined as death, relapse, non-engraftment, grade 3-4 aGVHD or extensive cGVHD) is superior for recipients of a TCD transplant than those receiving post transplant CY, when either is used as a CNl free GVHD prevention strategy. 2. Compare infection rates, toxicities and immune-reconstitution kinetics between transplant recipients receiving either TCD or post transplant CY. 3. Compare longitudinal symptom burden profiles among stem cell transplant recipients receiving either TCD or post transplant CY as GVHD prophylaxis. RELEVANCE (See instructions): The proposed trial will confirm the impact of immune-reconstitution on transplant outcomes. This will also be the largest study looking at longitudinal symptom burden in the setting of allogeneic HSCT. Data obtained from this study will be pooled together with other symptom burden studies to explore the potential relationship between genetic factors and development of symptom clusters.